Vita d defic insuffic pregnancy johnson am j perinatol 2010
Vitamin D Deﬁciency and Insufﬁciency isCommon during PregnancyDonna D. Johnson, M.D.,1 Carol L. Wagner, M.D.,2 Thomas C. Hulsey, D.Sc.,3Rebecca B. McNeil, Ph.D.,4 Myla Ebeling, R.A.,3 and Bruce W. Hollis, Ph.D.2ABSTRACT The objective was to determine the incidence of vitamin D deﬁciency, insufﬁ- ciency, and sufﬁciency in African-American, Hispanic, and Caucasian pregnant women. Blood samples were taken from 154 African-American, 194 Hispanic, and 146 Caucasian women at <14 weeks of gestation; 25 hydroxyvitamin D levels (25(OH)D) levels were Downloaded by: Stanford University. Copyrighted material. measured by radioimmunoassay. The mean 25(OH)D levels in African-American, Hispanic, and Caucasian pregnant women were 15.5 Æ 7.2 (standard deviation), 24.1 Æ 8.7, 29.0 Æ 8.5 ng/mL, respectively. Ninety-seven percent of African-Americans, 81% of Hispanics, and 67% of Caucasians were deﬁcient (25(OH)D levels <20 ng/mL or <50 nmol/L) or insufﬁcient (25(OH)D levels !20 ng/mL or <32 ng/mL or !50 nmol/L or <80 nmol/L). Of these pregnant women, 82% had vitamin D levels <32 ng/mL (<80 ng/mL). In logistic regression models, race was the most important risk factor for vitamin D deﬁciency or insufﬁciency. African-American women and Hispanic women were more likely to have vitamin D insufﬁciency and deﬁciency than Caucasian women. Furthermore, primigravid women were more at risk for vitamin D insufﬁciency. This study demonstrates widespread vitamin D deﬁciency and insufﬁciency in pregnant females living at a southern latitude. African-Americans are at greatest risk. KEYWORDS: Hypovitaminosis D, pregnancy, vitamin D W ith the identiﬁcation of increasing numbers have vitamin D deﬁciency deﬁned as less thanof children with rickets in the United States in the 37.5 nmol/L (<15 ng/mL).2 Follow-up data from1990s, the medical community exhibited a renewed NHANES in 2000 to 2004 demonstrated that vitamininterest in vitamin D deﬁciency and vitamin D research.1 D concentrations in the population have not improved.3One of the initial studies to assess the vitamin D status of Because women of reproductive age are deﬁcient inwomen of reproductive age used samples collected in the vitamin D, it was reasoned that pregnant women alsoNutrition Examination Survey (NHANES III) from are likely to be deﬁcient.1988 through 1994 to measure 25 hydroxyvitamin D Evaluation of vitamin D status of pregnantlevels (25(OH)D). Forty-two percent of African- women has been primarily done outside of the UnitedAmerican and 4% of Caucasian females were found to States in populations that are at signiﬁcant risk for1 Division of Maternal Fetal Medicine, Department of Obstetrics and 96 Jonathan Lucas Street, CSB 634, Charleston, SC 29425-0619Gynecology, Medical University of South Carolina; 2Division of (e-mail: firstname.lastname@example.org).Pediatric Nutrition, Department of Pediatrics, Children’s Research Am J Perinatol. Copyright # by Thieme Medical Publishers, Inc.,Institution; 3Division of Pediatric Epidemiology, Department of 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212)Pediatrics, Rutledge Tower, Charleston, South Carolina; 4Department 584-4662.of Biostatistics, Mayo Clinic, Jacksonville, Florida. Received: January 27, 2010. Accepted after revision: May 10, 2010. Address for correspondence and reprint requests: Donna D. DOI: http://dx.doi.org/10.1055/s-0030-1262505.Johnson, M.D., Division of Maternal Fetal Medicine, Department of ISSN 0735-1631.Obstetrics and Gynecology, Medical University of South Carolina,
AMERICAN JOURNAL OF PERINATOLOGYvitamin D deﬁciency, such as immigrants with dark skin and Caucasian pregnant women enrolled in a vitaminpigmentation living at very northern latitudes or women D supplementation trial and to report cumulativewho wear clothing that covers most of the body surface incidence of vitamin D deﬁciency (<20 ng/mL ordue to religious and cultural preferences.4–12 In a large <50 nmol/L), insufﬁciency (!20 ng/mL and <32 ng/mLEuropean study of 358 pregnant women, 8% of Western or !50 nmol/L and <80 nmol/L), and sufﬁciencyand 73% of Turkish, Moroccan, and other non-West- (!32 ng/mL or >80 nmol/L) in these three groups aterners were vitamin D deﬁcient, deﬁned as <25 nmol/L a southern (32.7 degrees north) latitude.(<10 ng/mL). This study was conducted in The Hague,Netherlands. This city lies at the 52 degrees northlatitude and is 3 degrees north of the most northern METHODSlatitude of the vast majority of mainland United States. Approval for this study was granted by the MedicalThe intensity of the sun is greatest at the equator and University of South Carolina’s Institutional Reviewdecreases at increasing latitudes.13 So, pregnant women Board for Human Subjects, HR No. 10727 and thein the United States would be expected to be less General Clinical Research Center (Protocol #670). Pa-deﬁcient than the Netherlands cohort because the sun tients from Charleston, South Carolina, who were lessis more intense, especially during the summer months, than 14 weeks of pregnancy were recruited and gaveand few American women wear clothing that fully covers consent over a 5-year period. Patients with diseasesthem. associated with defects in vitamin D such as sarcoid, A study of a pregnant cohort of 200 Caucasian renal disease, uncontrolled thyroid disease, or para-and 200 African-American pregnant women was thyroid disease were excluded from the study. In Downloaded by: Stanford University. Copyrighted material.recently conducted in Pittsburgh, Pennsylvania (40 addition, patients with chronic hypertension and dia-degrees north latitude). Vitamin D levels were meas- betes were excluded as patients with these diseases haveured at 4 to 21 weeks and at delivery. Five percent of a higher incidence of adverse pregnancy outcomes. TheCaucasian females and 29% of African-American vitamin D levels were obtained as baseline data duringfemales were found to be vitamin D deﬁcient as a large randomized clinical trial in which women weredeﬁned by a 25(OH)D level <37.5 nmol/L (<15 randomized to receive different amounts of vitamin Dng/mL). Forty-two percent of Caucasians and 54% supplementation during pregnancy. The primary ob-of African-Americans were found to have vitamin D jective of the trial was to determine the safety ofinsufﬁciency (25(OH)D 37.5 to 80 nmol/L; 15 to 32 higher-dose vitamin D supplementation in pregnancy.ng/mL). Overall, only 53% of Caucasians and 17% of Race was self-reported and classiﬁed as non-HispanicAfrican-Americans had adequate vitamin D levels or Hispanic black, Hispanic white, or non-Hispanic(>80 nmol/L or >32 ng/mL).14 Thus, despite being white. Throughout this article, the classiﬁcations arecloser to the equator, vitamin D deﬁciency or insufﬁ- referred to as African-American, Hispanic, and Cau-ciency in pregnant women is also prevalent in the casian. Demographic information was obtained at theUnited States. ﬁrst patient encounter. Prepregnancy maternal weight What then accounts for this high prevalence of was self-reported. Maternal height was measured atvitamin D deﬁciency and insufﬁciency? Vitamin D is the ﬁrst clinical visit. This information was used toobtained from diet, dietary supplements, and sunlight. calculate maternal prepregnancy body mass indexFew foods naturally contain vitamin D. In developed (BMI) in kg/m2.countries, some foods are fortiﬁed with vitamin D. The Whole blood was collected in serum separatoramount that food is fortiﬁed with vitamin D and the tubes and centrifuged. Serum was collected and thenamount of vitamin D in the typical dietary supplement stored at À808C and analyzed in batches. Total circulat-(400 IU) is inadequate to correct vitamin D deﬁciency.13 ing 25(OH)D levels were measured using radioimmuno-Cutaneous synthesis is the most important source of assay as previously described.16 The detection limit ofvitamin D. Regardless of the latitude, any process that the assay is 2.8 mg/L. The assay precision (coefﬁcientreduces or blocks absorption of ultraviolet B radiation of variation) was less than 7%.17 Laboratory personnelwill decrease the amount of vitamin D synthesized. For were blinded to sociodemographic data of the subject,example, the darker skin pigmentation commonly seen including race/ethnicity.in African-Americans decreases the amount of vitamin Subjects were classiﬁed using the followingD synthesized.15 Not surprisingly, a racial disparity in deﬁnitions. If their level of 25(OH)D was less thanvitamin D levels and deﬁciency has long been recog- <20 ng/mL (<50 nmol/L), the subjects were classiﬁednized. Although pregnant African-American and Cau- as vitamin D deﬁcient. If their levels were !20 butcasian females have been studied, very little is known <32 ng/mL (!50 nmol/L and <80 nmol/L), the sub-about the pregnant Hispanic population. The objective jects were classiﬁed as insufﬁcient. Only subjects withof this observational study was to compare the baseline serum levels of 25(OH)D !32 ng/mL (!80 nmol/L)vitamin D levels of African-American, Hispanic, were classiﬁed as having sufﬁcient vitamin D levels.17–19
VITAMIN D DEFICIENCY AND INSUFFICIENCY/JOHNSON ET ALTable 1 Demographics by Ethnicity African-American Hispanic CaucasianDemographics (n ¼ 154) (n ¼ 189) (n ¼ 146) p ValueMaternal age (mean, SD)* 25.3 Æ 4.9 24.8 Æ 4.8 30.1 Æ 5.4 <0.001Gestational age (mean, SD)* 11.6 Æ 2.3 9.5 Æ 2.1 10.7 Æ 1.8 <0.001Primigravida, n (%)y 28 (20%) 58 (36%) 52 (40%) <0.001BMI !30, n (%)y 64 (52%) 32 (22%) 23 (21%) <0.0001Season (April through September)y 69 (44%) 101 (53%) 60 (41%) NS*Analysis of variance.y Chi-square.BMI, body mass index; SD, standard deviation. Data were analyzed using SAS for Windows Americans were deﬁcient than either Hispanics or Cau-version 9.1. Categorical variables were analyzed using casians. Ninety-seven percent (149/154) of African-chi-square and continuous variables were analyzed using Americans, 81% (157/194) of Hispanics, and 67% (98/analysis of variance. A p value less than 0.05 deﬁned 146) of Caucasians were insufﬁcient or deﬁcient. Moresigniﬁcance. Multivariate analysis of the three categories Caucasians had normal vitamin D levels than the otherof vitamin D was conducted with multinomial logistic two groups; of those two groups, Hispanics were moreregression using Proc Logistic in SAS. This procedure likely than African-Americans to have normal vitamin Dallows the modeling of the dependent variable as a levels. Downloaded by: Stanford University. Copyrighted material.three-group categorical variable (vitamin D <20 ng/mL Table 2 presents the results of the logistic regres-[<50 nmol/L], vitamin D !20 to <32 ng/mL sion modeling for vitamin D deﬁciency, insufﬁciency,[!50 nmol/L and <80 nmol/L], vitamin D !32 ng/mL and sufﬁciency. Controlling for these potential con-[!80 nmol/L]) as a function of the independent variables founders (maternal age, parity, race, BMI !30, andage, parity, ethnicity, obesity (BMI >30), and sunlight enrollment during summer months), African-Americanexposure. The results of this analysis present an odds ratio and Hispanic women were persistently at greater risk forand 95% conﬁdence interval for the association of each either vitamin D deﬁciency or insufﬁciency than Cau-independent variable with the two categories of vitamin casians. Of the included covariables, only primigravidD deﬁciency (<20 ng/mL or <50 nmol/L) and vitamin women were signiﬁcantly at risk for vitamin D insufﬁ-D insufﬁciency (20 to 32 ng/mL or >50 nmol/L and ciency.<80 nmol/L), considering vitamin D sufﬁciency(!32 ng/mL or !80 nmol/L) as the reference category. DISCUSSION This study clearly demonstrates a high incidence ofRESULTS vitamin D deﬁciency and insufﬁciency and in womenDemographic data are presented in Table 1. Caucasian during their ﬁrst trimester of pregnancy in a city in thewomen were older than either African-Americans or United States with high UV index. The incidence ofHispanics. Caucasians and Hispanics were more likely to vitamin D deﬁciency and insufﬁciency in this populationbe primigravid than African-Americans. More African-Americans were obese than either Caucasians or His-panic women. The average gestational age at enrollmentwas less than 12 weeks in all groups, but Hispanicwomen were enrolled at an earlier gestational age thanthe other two groups. Samples were drawn as frequentlyin the spring and summer compared with fall and winter. The mean 25(OH)D levels in African-Americans, Hispanics, and Caucasians were 15.5Æ7.2(standard deviation), 24.1Æ8.7, 29.0Æ8.5 ng/mL, re-spectively. The range for African-Americans was 2.4 to43.5 ng/mL, for Hispanics was 6.2 to 52.9 ng/mL, andfor Caucasians was 9.3 to 69.0 ng/mL. Forty-one percent(200/494) of all pregnant women were deﬁcient, andan additional 41% (204/494) were insufﬁcient. Overall, Figure 1 Vitamin D deﬁciency (<20 ng/mL or <50 nmol/L,82% of this cohort had vitamin D levels <32 ng/mL black bar) is more common in African-Americans, and vitamin(<80 nmol/L). Figure 1 displays vitamin D deﬁciency, D sufﬁciency (!32 ng/mL or !80 nmol/L, white bar) is moreinsufﬁciency, and sufﬁciency by race. More African- common in the Caucasian population.
AMERICAN JOURNAL OF PERINATOLOGYTable 2 Multinomial Logistic Regression Model for Vitamin D LevelsVariable Vitamin D Group Odds Ratio 95% CI p ValueAge <25 y <20 1.38 0.62–3.06 0.43 20–31 0.86 0.41–1.81 0.70 32þ 1.00 (ref) — –—Primigravida <20 2.17 0.95–4.97 0.07 20–31 3.18 1.56–6.49 0.001 32þ 1.00 (ref) — —Black (versus white) <20 54.98 16.37–184.62 <0.0001 20–31 3.24 1.04–10.07 0.04 32þ 1.00 (ref) — —Hispanic (versus white) <20 5.25 2.10–13.17 0.004 20–31 2.06 1.03–4.11 0.04 32þ 1.00 (ref) — —Obese (BMI !30) <20 1.87 0.81–4.28 0.14 20–31 1.66 0.78–3.52 0.19 32þ 1.00 (ref) — —Summer months <20 0.80 0.39–1.61 0.52 20–31 0.94 0.51–1.73 0.83 Downloaded by: Stanford University. Copyrighted material. 32þ 1.00 (ref) — —BMI, body mass index; CI, confidence interval.is higher than or similar to the incidence reported in amount of time outside and the use of sunscreens inother studies conducted in an adult population when this study. Because of the heat index, subjects maysimilar deﬁnitions for vitamin D deﬁciency, insufﬁ- spend less time outside in the summer compared withciency, and sufﬁciency is used.14 Skin pigmentation, the other seasons. Also, African-Americans have aand thus race and ethnicity, inﬂuence the amount of smaller increase in vitamin D levels than Caucasiansvitamin D synthesis from sun exposure. Persons with with the same amount of sun exposure.20 Finally, ourdarker skin synthesize less vitamin D for a given ex- population may have been so deﬁcient that the amountposure and are, not surprisingly, more prone to vitamin of sun exposure did not signiﬁcantly impact their levels.D deﬁciency.15 In the U.S. study conducted in Pitts- In Florida, female subjects only experience a 13%burgh, Pennsylvania, 83% of blacks and 47% of whites increase in their 25(OH)D levels between winter andhad insufﬁcient or deﬁcient vitamin D levels.14 This summer.21observation is consistent in our population where 97% of Obesity is also a known risk factor for vitamin DAfrican-Americans and 67% of Caucasians had vitamin deﬁciency.22–25 The etiology of this association is un-D deﬁciency or insufﬁciency. Because Hispanics have clear. Several hypotheses have been proposed. Peopledarker pigmentation than Caucasians and generally with a higher BMI may avoid sunbathing or adiposelighter pigmentation than blacks, the expected frequency tissue may sequester vitamin D.23 Also, obesity may notof vitamin D deﬁciency or insufﬁciency in pregnant affect the vitamin D status of all races equally.23,25 In ourHispanics should be greater than Caucasians but less cohort, we deﬁned obese patients (BMI !30) and non-than African-Americans. Indeed, this observation has obese patient (BMI 30) and using this cut-point forbeen made in the general population and was also obesity in our cohort, obesity was not a risk factor forconﬁrmed in our pregnancy population.3 In fact, race/ deﬁcient or insufﬁcient vitamin D levels. Others haveethnicity is the variable most strongly associated with compared obese patients (BMI !30) to patients withvitamin D levels in our population. normal weight (BMI 25).22,24 In our study, including Seasonality has long been recognized as an im- the overweight individuals may have blunted the effectportant modulator of vitamin D status. Subjects have of obesity on vitamin D levels.higher 25(OH)D levels in the summer than in In our study, primigravid subjects were morethe winter.13 For example, above 35 degrees north likely to have deﬁcient or insufﬁcient vitamin D levelslatitude (Atlanta, Georgia), little or no vitamin D can than multiparous subjects. In most studies, parity has notbe produced from November to February.13 In our been examined in relationship to vitamin D. In thestudy, seasonality was not a signiﬁcant covariable in largest U.S. study, the majority of blood samples wereour population. Others have noted no impact of season- obtained only from primigravid women and all of theirality on 25(OH)D levels in their population.12 Several patients were nulliparous (i.e., had not delivered a childexplanations are possible. We did not examine the >20 weeks).14 In the largest European trial with
VITAMIN D DEFICIENCY AND INSUFFICIENCY/JOHNSON ET AL358 subjects, parity was not signiﬁcant.12 Parity was Saudi mothers and their neonates. Pediatr Res 1984;18:speciﬁcally studied in 86 Saudi pregnant women; how- 739–741ever, the authors compared patients who were para 5 to 5. Brooke OG, Brown IR, Cleeve HJ, Sood A. Observations on the vitamin D state of pregnant Asian women in London. Brsubjects who were para 4 or less, and in this comparison, J Obstet Gynaecol 1981;88:18–26parity did not affect vitamin D levels.26 In our popula- 6. ´ Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, ¨tion, primigravid women may have different habits than Lemeur H. Vitamin D supplementation in pregnancy: amultiparous women. We did not examine the relation- controlled trial of two methods. Obstet Gynecol 1986;68:ship of parity to diet, sun exposure, and supplementation 300–304use in this analysis. 7. Brunvand L, Haug E. Vitamin D deﬁciency amongst There is no consensus on the optimal levels of Pakistani women in Oslo. Acta Obstet Gynecol Scand 1993; 72:264–26825(OH)D. Most experts agree that vitamin D deﬁciency 8. ˘ ˘ ¨ Pehlivan I, Hatun S, Aydogan M, Babaoglu K, Gokalp AS.is <20 ng/mL (50 nmol/L), and this is the deﬁnition we Maternal vitamin D deﬁciency and vitamin D supplementa-used in our population.13 We chose to deﬁne vitamin D tion in healthy infants. Turk J Pediatr 2003;45:315–320insufﬁciency as <32 ng/mL (80 nmol/L). Recent data 9. O’Riordan MN, Kiely M, Higgins JR, Cashman KD.suggest that a cutoff of <32 ng/mL (80 nmol/L) is more Prevalence of suboptimal vitamin D status during pregnancy.appropriate based on the measurement of speciﬁc bio- Ir Med J 2008;101:240, 242–243markers that increase or decrease with changes in 10. Datta S, Alfaham M, Davies DP, et al. Vitamin D deﬁciency in pregnant women from a non-European ethnic minority25(OH)D levels, such as parathyroid hormone, calcium population—an interventional study. BJOG 2002;109:absorptions, and bone mineral density.18,27,28 Because 905–908the fetus is entirely dependent on maternal stores for Downloaded by: Stanford University. Copyrighted material. 11. Serenius F, Elidrissy AT, Dandona P. Vitamin D nutrition invitamin D, adequate vitamin D levels during pregnancy pregnant women at term and in newly born babies in Saudiare essential. The vitamin D level in the fetus is $50 to Arabia. J Clin Pathol 1984;37:444–44760% of maternal concentrations.29 Several small studies 12. van der Meer IM, Karamali NS, Boeke AJP, et al. Highsuggest that inadequate vitamin D intake may be asso- prevalence of vitamin D deﬁciency in pregnant non-Western women in The Hague, Netherlands. Am J Clin Nutr 2006;ciated with adverse pregnancy outcomes, such as intra- 84:350–353; quiz 468–469uterine growth restriction and preeclampsia.30,31 13. Holick MF. Vitamin D deﬁciency. N Engl J Med 2007;However, currently there are no randomized trials that 357:266–281examine the affect on maternal or fetal outcomes using 14. Bodnar LM, Simhan HN, Powers RW, Frank MP,the cutoffs used in this study. Cooperstein E, Roberts JM. High prevalence of vitamin D In summary, the incidence of vitamin D is deﬁ- insufﬁciency in black and white pregnant women residing inciency and insufﬁciency is very high in early pregnancy in the northern United States and their neonates. J Nutr 2007;137:447–452a southern city in the United States. Our ﬁndings are 15. Matsuoka LY, Wortsman J, Haddad JG, Kolm P, Hollissimilar to other pregnant populations in the United BW. Racial pigmentation and the cutaneous synthesis ofStates and Europe. As in the nonpregnant population, vitamin D. Arch Dermatol 1991;127:536–538African-American women are the most severely affected 16. Hollis BW. Comparison of equilibrium and disequilibriumfollowed by Hispanics and then Caucasians.3 More assay conditions for ergocalciferol, cholecalciferol and theirresearch is necessary to determine the optimal vitamin major metabolites. J Steroid Biochem 1984;21:81–86D levels during pregnancy and adequate vitamin D 17. Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL. Determination of vitamin D status by radioimmunoassaysupplementation in pregnant females. with an 125I-labeled tracer. Clin Chem 1993;39:529–533 18. Hollis BW. Circulating 25-hydroxyvitamin D levels indica- tive of vitamin D sufﬁciency: implications for establishing aREFERENCES new effective dietary intake recommendation for vitamin D. J Nutr 2005;135:317–322 1. Sills IN, Skuza KA, Horlick MNB, Schwartz MS, Rapaport 19. Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent R. Vitamin D deﬁciency rickets. 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